Juvenile myelomonocytic leukemia (JMML) is a rare, clonal myeloproliferative disorder afflicting young children. Since 1986 a team of investigators at the University of Alabama at Birmingham (UAB) have been conducting translational research studies in JMML. Over the last ten years the UAB JMML project has risen to the forefront of research in this rare but fascinating disorder. The blend of investigators in basic science and clinical investigation has positioned the UAB team in a unique role to have unprecedented access to JMML patients and thus take a leadership role in investigating mechanism-based treatment modalities. The pathogenesis of JMML has been linked to deregulated GM-CSF growth factor signal transduction through the Ras pathway. This deregulation results in JMML cells demonstrating selective hypersensitivity to GM-CSF in vitro. This feature of growth factor hypersensitivity is emerging as a potential common mechanism amongst many other myeloproliferative disorders and thus, JMML serves as an important model disease. Potential causative mutations resulting in GM-CSF hypersensitivity include neurofibromatosis gene abnormalities in 30 percent of JMML patients and RAS mutations in an additional 20 percent of patients. Causative mutations are undefined in the remaining majority of patients. In addition to providing insights into the pathogenesis of this disease, the UAB JMML project has also identified a promising new treatment modality using 13-cis retinoic acid (CRA). The retinoic acid appears to modulate the hypersensitive GM-CSF response in JMML. But CRA does not appear to be effective enough to induce complete, lasting remissions. Thus there is a need for more effective therapeutics and such strategies can be aimed at the GM-CSF pathway as a result of the pathogenetic studies. The major goals for the recipient of this K24 award will be: (1) to establish the first North American JMML Registry at the P.I.'s institution and the first Pediatric Intergroup Multimodality Clinical Trials Program for JMML, (2) to complete the development of a diagnostic test for JMML, field test it and implement it, (3) to continue to investigate for other genetic mutations in the Ras signaling pathway responsible for GM-CSF hypersensitivity within JMML cells, and (4) to develop other novel therapeutic strategies for JMML that are mechanism-based.